The overall goal of this application is to discover and develop medications for the treatment of substance abuse. However, we expect that the compounds developed will also serve as biochemical probes useful in gaining a better understanding of the biochemical and molecular mechanisms of opiate addiction and withdrawal. The specific aim is to develop potent and subtype selective mu, delta, or kappa opioid pure antagonists. The scope of our approach will involve the design, synthesis, and biological evaluation of target compounds based on the N- substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine and BW373U86 class of opioid compounds. The scope of each study will include: (1) the development of testable models for opioid antagonist activity and subtype selectivity; (2) the design and synthesis of compound libraries followed by specific target compounds; (3) in vitro evaluation of the libraries and target compounds using radioligand and [35S]GTPgammaS binding assays; and (4) in vivo evaluation in animal models. Compounds that show potent and selective affinity at the mu and delta receptors will be evaluated for their ability to upregulate surface receptors by Dr. Chris Evans (UCLA). Compounds which show greater potency as antagonists in the [35S]GTPgammaS assay relative to the radioligand binding assay will be evaluated as inverse agonists by Dr. John Traynor (U. of Michigan). Behavioral studies will be conducted by Dr. Toni Shippenberg (NIDA-ARC) and Dr. Linda Dykstra (U. of North Carolina); selected compounds will be evaluated for suppression of ethanol-reinforcing responding in rats and rhesus monkeys by Dr. Harry June (U. of Indiana) and Dr. James Wood (U. of Michigan), respectively; high affinity kappa selective compounds will be submitted to the NIDA Opioid Treatment Discovery Program for both in vitro and in vivo activity, and compounds showing Ki values less than 100 nM will be submitted to the CPDD testing program. At present, few potent, systematically active and selective nonpeptide antagonists are available. The design and synthesis of novel selective nonpeptide opioid receptor antagonists will provide critically needed tools to advance our understanding of the role of the opioid receptor/endorphin system in both normal and various disease states, including dru2g addiction. In particular, we propose that the development of selective delta and kappa antagonists may provide a new generation of important investigational drugs and possible treatment drugs for people suffering from drug addiction.